Alpha, alpha-dimethyl-beta, beta-dimercapto-n-lower alkyl-(phenyl and substituted phenyl) ethylamines

ABSTRACT

Dimercapto compounds characterized as alpha, alpha-dimethylbeta, beta-dimercapto-N-lower alkyl-(phenyl and substituted phenyl) ethylamines of the structural formula: WHERE R is phenyl and substituted phenyl and R1 is lower alkyl containing one to eight carbon atoms are described. Trithiolane condensation derivatives of the dimercapto compounds (I) prepared by oxidation with the elimination of hydrogen sulfide are also described. The dimercapto compounds (I) are generally prepared by reacting an alpha, alpha-dimethyl-beta-N-lower alkyl imine(phenyl and substituted phenyl) ethylamine of the structural formula: WHERE R and R1 are as in the dimercapto compounds (I) and R2 is a lower alkyl group containing one to eight carbon atoms with hydrogen sulfide in an inert anhydrous polar organic solvent for the imino compounds (III) at temperatures less than the decomposition temperature of the dimercapto compounds (I) and until (I) is formed and precipitates from the reaction mixture. The imino compounds (III) are preferably prepared by reacting a compound of the structural formula: WITH A LOWER ALKYL AMINE (R2-NH2) containing one to eight carbon atoms. The product dimercapto compounds (I) and trithiolanes are particularly useful as antimalarials in mammals.

United States. Patent Ash et al.

[54] ALPHA,.ALPHA-DIMETHYL-BETA, BETA-DIMERCAPTO-N-LOWER AL-KYL-(PHENYLAND SUBSTITUTED PHENYL ETHYLAMINES Inventors: Arthur B. Ash, LathrupVillage;

Calvin L. Stevens, Detroit, both of Mich [1310 [221 Filed:' Sept. 11,1970 Related Application Data Division of Ser. No. 809,012, March 20,1969, Pat-N0. 3,578,682. 1

US. Cl...;,.....2 60/570.5 S, 260/327, 260/348 R, 260/348.6, 260/50l.2l,260/566 R, 260/566 .D, 260/570.5 C, 260/570.8 R, 260/592, 424/277,424/330 Int. Cl ..C07c 87/28 Field of Search ..260/570.5 S

1,354,813 2/1964 France ..260/570.5

OTHER PUBLICATIONS Magnusson, Acts Chem. Scand.," Vol, 17, pages 273 275(1963).

Primary. Examiner-Robert V. Hines Altbrney-Miller, Morris, Poppas &McLeod and lan C. McLeod [5 7] ABSTRACT Dimercapto compoundscharacterized as alpha, alphadimethyl-beta, beta-dimercapto-N-loweralkyl-(phenyl and substituted phenyDe'thylamines of the structuralformula: V

Assignee: Ash Stevens,lnc., Detroit, Mich. I

4421 Sept. 26, 1972 SH CH3 R- -NHRi where R is phenyl and substitutedphenyl and R, is lower alkyl containing one toeight carbon atoms aredescribed. Trithiolane condensation derivatives of the dimercaptocompounds (l) prepared by oxidation with the elimination of hydrogensulfide are also described. The dimercapto compounds (I) are generallyprepared by reacting an alpha, alpha-dimethyl-beta-N-lower alkylimine-(phenyl and substituted phenyl) lhy minsa th c f mula NR2 CH3 In-o- NHR1 where R and R, are as in the dimercapto compounds (I) and R, isa lower alkyl group containing one to eight carbon atoms with hydrogensulfide in an inert anhydrous polar organic solvent for the iminocompounds (III) at temperatures less than the decomposil0l'l temperatureof the dimercapto compounds (I) and until (I) is formed and precipitatesfrom the reaction mixture. The imino compounds (lll) are preferablyprepared by reacting a compound of the structura qr ula 0 CH3 (II) RNHR-l a. t .H r

with a lower alkyl amine (R -NH containing one to eight carbon atoms.The product dimercapto compounds (I) and trithiolanes are particularlyuseful as antimalarials in mammals.

' 5 Claims, No Drawings ALPHA, ALPHA-DIMETHYL-BETA, BETA-DIMERCAPTO-N-LOWER ALKYL-(PHENYL AND SUBS'I'II'IJTED PHENYL) ETHYLAMINESThis application is adivisional of our earlier application Ser. No.809,012, filed 1969 Mar. 20, now U.S. Pat. No. 3,578,682.

BACKGROUND OF THE INVENTION structural formula:

whereR is'plienyl and substituted phenyl and R is lower alkyl containingone to eight carbon atoms, their preparation and use as antimalarialcompounds.

The dimercapto compounds (I) are not known to the prior art. Mercaptocompounds are not known to be useful as antimalarials. The preparationof unrelated dimercapto compounds for other uses is known to the priorart. In general, the corresponding keto or imino compound is reactedwith hydrogen sulfide to form the dimercapto compound. Prior artreferences showing such reactions are: T. L. Cairns, et al, J. Am. Chem.Soc. 74, 3982 (1952); G. A. Buchtold, et al, J. Am. Chem. Soc. 81, 3148(1959); E. Campaigne, e al, J. Org. Chem}, 27, 3760 (1962); C. Djerassi,et al, J. Org. Chem. 27, 1041 (1962); M. Demuynck et al, Bull. Chim.500., France 2126 (1962); French Patent No. 1,354,813; German Patent No.1,173,894; Netherlands Application 284,140 (1964); B. Magnusson, Acta.Chem: Scand. 17, 273 (1963); and H. Barrea, et al, J. Org. Chem. 27, 641(1962). None of these prior art references show a reaction of hydrogensulfide with secondary amino compounds (a basic group) such as thealpha, alpha-dimethyl-beta-N-lower alkyl imine- (phenyl and substitutedphenyl) ethylamines (111) preferably used as starting materials in theprocess of the present invention.

8 OBJECTS SUMMARY OF THE INVENTION The present invention relates toalpha, alphadimethyl-beta, beta-dimercapto-N-lower alkyl-(phenyl andsubstituted phenyl) ethyl-amines which are particularly useful asantimalarials in mammals of the rustmal ormukafi S H OH:

R- -NH B1 wherein R is phenyl and substituted phenyl such as, ortho,meta and para substituents preferably halo (fluro, chloro, iodo andbromo) substituents. The present invention also relates to trithiolanederivatives of the dimercapto compounds (1) of the present inventionwhich have been found to be active as antimalarials characterized as2,5-di-(phenyl and substituted phenyl)-2,5-bis-(2-N-lower alkyl aminoisopropyl)-l,3,4- trithiolane and non-toxic pharmaceutically acceptableacid addition salts thereof of the structural formula:

wherein R and R, are as in the dimercapto compound (I). Non-toxic salts(HX) include those formed by acids such as hydrochloric, hydrobromic,sulfuric, phosphoric, acetic, tartaric, citric, p-toluene sulfonic acidand the like although hydrochloric is preferred.

The dimercapto compounds (I) of the present invention are prepared bythe process which comprises reacting an alpha,alpha-dimethyl-beta-N-lower alkyl imine-(phenyl and substituted phenyl)ethylamine of the structural formula:

(III) wherein R and R are as before and R is lower alkyl containing oneto eight carbon atoms with hydrogen sulfide in an inert anhydrous polarorganic solvent for the imino compound (III) at temperatures less thanthe decomposition temperatures of the dimercapto compound (I) until thedimercapto compound (I) precipitates from the reaction mixture. Thereaction is generally conducted at a temperature between about 10 and30C in a polar organic solvent such as ethanol or other lower alkanolscontaining one to eight carbon atoms wherein the product dimercaptocompound (I) is insoluble inthe solvent and precipitates from thereaction mixture. Preferably the preparation of the product (I) isstarted from an alpha-lower alkyl amino isobutyro substituted andunsubstituted phenyl ketone of the structural formula:

which is reacted with a lower alkyl amine containing one to eight carbonatoms (RgNHg) to form the imino compound (I11) since these ketones (11)are more readily available as shown for instance by U.S. Patent No.

3,082,255 and Stevens et al, J. Org. Chem. 27, 4392 (1962). It is mostpreferred to conduct the reaction of the ketone (II) with the loweralkyl amine (R NH and the subsequent reaction of the imine (III) withhydrogen sulfide by eliminating the steps of separation and purificationof the imine (111) from the reaction mixture.

The trithiolanes (la) are derived from the dimercapto compounds (I) andcan be produced by allowing the dimercapto compounds (I) to be exposedto the atmosphere for a long period of time. Essentially, the reactionproceeds by the elimination of hydrogen sulfide with condensation of twomolecules of the dimercapto compound (I) and by the oxidative formationof the sulfur to sulfur bond. It has been found that this reaction canbe accelerated by heating with or without polarorganic solvent or bysubjecting the dimercapto compound (I) to oxidative conditions or bothas described more fully hereinafter.

DESCRIPTION OF THE INVENTION The following equations illustrate thepreferred sequence of reactions used to prepare the dimercapto compounds(I) and trithiolane derivatives (la) starting from the ketones (II):

ducted either in an alcohol solvent or in a closed system, since thelower alkyl amines are gaseous at elevated temperatures. The reactiontemperature range is generally between about 70 and 150C. Reaction 2 isconducted by adding gaseous hydrogen sulfide to a solution of III in apolar organic solvent at a temperature usually between about and 30Cwhich is less than the decomposition temperature of the dimercaptocompound (I). (I) precipitates from the reaction mixture as acrystalline solid at ambient or lower temperatures. Reaction 3 proceedsat temperatures between about 25 and 100C with elimination of hydrogensulfide by an oxidative formation of the sulfur to sulfur bond in whichthe element hydrogen is eliminated, probably as water.

Having generally described the present invention the following is aspecific description.

SPECIFIC DESCRIPTION The following Examples 1 to 3 illustrate theprocess for the preparation of the antimalarial compounds of the presentinvention. Temperatures are given in degrees Centigrade.

EXAMPLE I Synthesis of alpha, alpha-dimethyl-beta,beta-dimercapto-N-butyl phenethylamine and trithiolane.

A solution of 22.0 grams of N-butyl-beta-( butylimino)-alpha,alpha-dimethyl phenethylamine (C. L. Stevens and C. H. Chang, J. Org.Chem. 27, 4392 (1962) in 150 ml. of ethyl alcohol (J. T. Baker reagentgrade, denatured No. 3A) was placed in a 2-necked flask equipped with agas dispersion tube and gas outlet tube (no-drying tube). Hydrogensulfide was passed through the solution at 25 at a rate such that mostof the gas was absorbed. The solution temperature increased slightlyduring the addition. After about one hour, a solid crystallized from thesolution. Hydrogen sulfide addition was continued for another 30minutes. The solution was allowed to stand under a nitrogen atmospherefor one hour at 25,followed by 20 minutes at 0. The crystalline materialwas filtered, washed with 100 ml. of ethyl alcohol and dried for twohours at 25 to give 17.0 grams (77 percent yield) of a powdery yellowsolid, melting point 123- with evolution of hydrogen sulfide.

Analysis: Calculated for: C H NS C 62.40; H 8.60; N 5.20; S 23.80.Found: C6242; H8.67; N5.42; $23.73.

Minimum exposure of the product to the atmosphere is recommended toprevent the formation of the corresponding trithiolane. A rubber dam wasused during filtration to minimize exposure to air. The product isinsoluble in ether, ethanol, water, acetone and common organic solvents.Storage under nitrogen at -20 to 0 is recommended.2,5-Diphenyl-2,5-bis-(2-N butylaminoisopropyl)- 1 ,3 ,4-trithio1anedihydrochloride The dimercapto compound prepared in the first part ofthis Example (5g), was refluxed with ethanol (100ml.) for one hour. Asmall amount of insoluble material was separated by filtration. Theclear yellow filtrate was concentrated to give a yellow oil. The oil wasdissolved in ether 100ml.) and treated with a saturated solution ofhydrogen chloride in isopropanol. A white precipitate, 0.45g, meltingpoint l202, was obtained which was recrystallized from ethanol/ether togive 0.4g. of colorless trithiolane dihydrochloride, melting point 21621 8, decomposition.

Analysis: Calculated for C H N S CI C, 58.40; H, 7.65; N, 4.87; C],12.34; S, 16.70. Found: C, 58.53; H, 8.05; N, 4.78;C1, 12.93;S, 16.19.

EXAMPLE 2 Synthesis of alpha, alpha-dimethyl-beta,betadimercapto-N-n-butyl-p-chlorophenethylamine and trithiolane.

N-n-Butyl-beta-n-butylimino-alpha, alpha-dimethyl-pchlorophenethylamineN-Butylamine (480 grams, 6.58 moles), ethanol (1,200 ml.) and1,2-epoxy-l-methoxy-2-methyl-l-pchlorophenylpropane (600 grams, 2.82moles) were alpha,

.butyl-pschlorophenethylamine added to a 3-lit'er flask and refluxed for48 hours. Solvents were removed under reduced pressure and fresh ethanol(1,200 ml.) and n-butylamine (600 grams) added. The mixture was refluxedan additional 48 hours, stripped and the product distilled. There wasob- 2' A solution of .N-n-butyl-beta-n-butylimino alpha,alpha-dimethyl-p-chlorophenethylamine (150 grams, 0.487 mole) in ethanol(750 ml.) was saturated with stirring at room temperature, with hydrogensulfide. The resultant precipitate, a light yellow solid, was collectedby filtration and washed with anhydrous ethanol. The solid wasthenslurried in anhydrous ethanol (800 ml.). The product was collectedagain by filtration and dried in vacuo at room temperature. Afterthorough drying, the product weighed 114 grams (78 percent), meltingpoint l20121.5. The product should be stored in a cold box or arefrigerator under an inert gas atmosphere.

Analysis: Calculated for C H CINS C, 55.33; H, 7.30; N, 4.61; C], 11.67;S, 21.10. Found: C, 55.05; H, 7.20; N, 4.40; Cl, 11.90; S, 20.90.

Preparation of starting materials. pachloroisobutyrophenone:

To a 3-liter, 3-necked flask outfitted with stirrer, condenser andaddition funnel were added magnesium turnings (56.0 grams, 2.3 g atoms)and a small amount of ether (50 ml. A solution of p-bromochlorobenzene(430 grains, 2.25 moles) in ether (1 liter) was added slowly over a 2hour period. After the Grignard mixture was refluxed for 1' hour,isobutyronitrile (156 grams, 2.26 moles) in ether was added slowly. Themixture solidified when the addition was nearly completed.

More :ether. (100 ml.). was added and the yellow heterogeneous mixturewas refluxed for 2 hours. Dilute hydrochloricacid (6N, 1 liter) wasadded slowly and the mixture was refluxed for 5 hours. The layers wereseparated. The aqueouslayer was extracted with two portions of benzene(400 ml. each). The combined orgarlic extracts were washed successivelywith water, saturated potassium carbonate and saturated sodium chloride.After drying (MgS0 and removal of solvents, distillation afforded 342grams (83%) of pchloroisobutyrophenone, boiling point 80/1.25 mm.alpha-Bromo-p-chloroisobutyrophenone:

Carbon tetrachloride (500 m1.) and p-chloroisobutyrophenone (330 grams,1.8 mole) were placed in a 3- liter, 3-necked flask. A solution ofbromine (290 grams, 1.8 mole) in carbon tetrachloride (200 ml.) wasadded slowly. After the liberated HBr was removed under reducedpressure, the mixture was washed successively with water, sodiumthiosulfate solution and distilled water. Residual water was removed byazeotropic distillation with the carbon tetrachloride. Distillationyielded 468 grams (97 percent), boiling point 8l/0.03 mm, ofalpha-bromo-p-chloroisobutyrophenone.

1 ,2-Ep0xy-1*methoxy-2-methyll-p-chlorophenylpropanez' To a solutionml.) of sodium methoxide in methanol (25 percent) at 0- (ice bath) wasadded alpha-bromo-p-chloroisobutyrophenone (68 grams, 0.26 mole) inmethanol (60 ml.). The mixture was stirred 30 minutes at ice bathtemperature after the addition was completed. The mixture was pouredover ice and extracted with petroleum ether (three times, 150 ml.). Theextracts were washed with ice-water and dried (MgSO Distillation gave44.5 grams (76 percent) of the epoxyether, boiling point 58-59/0.25 mm.

Preparation of Trithiolane:

2,5-Di-( p-chlorophenyl )-2,5-bis-( 2-N-butylaminoisopropyl)- l,3,4-trithiolane dihydrochloride 2.

The title compound was prepared by the four following procedures fromalpha, alpha-dimethyl-beta,betadimercapto-N-n-butyl-p-chlorophenethylamine prepared above.

The products isolated from all four procedures, were identical in allrespects, as established by undepressed mixture melting points andidentical infrared spectra.

The corresponding 2,5-dipheny1 analog (without a chlorine atom in thepara position), was also prepared by the first procedure as can be seenfrom Example 1.

1. Heating a suspension of compound (I) in ethanol The dimercaptocompound prepared in the first part of this Example 2 (10 grams) wassuspended in ethanol (400 ml.) and refluxed on a steam bath for onehour. The reaction mixture was cooled, filtered and the clear filtratewas concentrated under reduced pressure. The residue was dissolved inether (400 ml.), filtered to remove a small amount of a solid, and thefiltrate was treated with a saturated solution of hydrogen chloride inisopropanol. A white precipitate was separated and recrystallized fromethanol/ether to give 280 mg. of trithiolane dihydrochloride, meltingpoint 218220. The mother liquors were combined, evaporated to drynessand recrystallized several times from ethanol/ether to give 700 mg. oftrithiolane dihydrochloride, melting point 216-21 8. A sample foranalysis was obtained by recrystallization from ethanol/ether, meltingpoint 218220.

Analysis: Calculated for C H Cl N S C, 52.17; H, 6.57; N, 4.35; S,14.92. Found: C, 52.23; H, 6.75; N, 4.46; S, 14.95.

2. Heating compound (1) neat at 80 The dimercapto compound (1.1 g) wasplaced on a watch-glass and placed in an oven at 80 for 16 hours. A red,gummy material was obtained which was dissolved in ether. An insolubleportion (20 mg.) was removed by filtration. The clear ethereal filtratewas treated with isopropanol-hydrogen chloride to give the trithiolanedihydrochloride mg) which was identical in all respects with thetrithiolane dihydrochloride obtained under procedure (1). a 3. Passingair through a suspension of compound (I) The dimercapto compound (1 g)was suspended in ethanol (50 ml.) at room temperature and a stream ofair was bubbled through the suspension. Hydrogen sulfide was evolvedimmediately; this was detected by col-' lecting the evolved gas in asolution of lead acetate to form insoluble lead sulfide. After one hour,gas evolution ceased. The reaction solution was evaporated to dryness.The resulting oily residue was converted to the trithiolanedihydrochloride salt as described under procedure (1). The yield was 150mg, melting point 218-220 (ethanol/ether). The product was identical inall respects with the compounds obtained by methods (1) and (2). 4.Heating of dimercapto compound (1) in isopropanolhydrogen chloride Thedimercapto compound (I) (5g) prepared in the first part of this Example,was dissolved in isopropanol saturated with dry hydrogen chloride (50ml.). The solution was heated on a steam bath for two hours while a slowstream of air was bubbled through the solution. After cooling to roomtemperature, the solvent and hydrogen chloride were removed underreduced pressure and a fresh isopropanol (20 ml.) was added to theresidue. After refrigerating for several hours, the white precipitatewas separated and washed with cold isopropanol/ether. The yield was 2.2g (41 percent), melting point 218-220 decomposition. The product wasidentical in all respects with the ones obtained under procedures 1 to3.

EXAMPLE 3 Preparation of alpha, alpha-dimethyl-beta,betadimercapto-N-ethyl-p-chlorophenethylamine.

The above dimercapto compound was prepared by the same reaction sequenceused for the synthesis of the n-butyl analog of Example 2.

l-( p-Chlorophenyl )-2-methy1-2-ethylamino-propanehydrochloride:

A solution, prepared from 1,2-epoxy-l-methoxy-2- methyl-l-p-chlorophenylpropane of Example 2, (10.5 grams, 0.05 mole), anhydrous ethylamine (4.5grams, 6.6 ml, 0.1 mole) and anhydrous ethanol (30 ml), was refluxed for48 hours. Solvent and excess ethylamine were removed under reducedpressure. The residue was treated with 3N aqueous hydrochloric acid. Acolorless precipitate separated which was leached with ether to removeany unreacted epoxyether. The precipitate was then washed with coldwater, dried in vacuo and recrystallized from ethanol/ether. The yieldof the amino propanone as the hydrochloride, based on the epoxyether,was 8.2 grams (62 percent), melting point 29 l-293.

Analysis Calculated for C H C1 NO: C, 54.97; H, 6.54; N, 5.34; CI,27.05. Found: C, 55.11; H, 7.78; N, 5.37; Cl, 27.09.

Pure aminopropanone as the hydrochloride (8 grams) was suspended in 10percent aqueous sodium hydroxide and the suspension was extracted withether. The ether layer was washed with water, dried (K CO and thesolvent was evaporated to give 6 grams of the aminopropanone as the freebase, as an oil. The oil was used in the next reaction without furthertreatment. alpha, alpha-dimethyl-beta,beta-dimercapto-N-ethylp-chlorophenethylamine:

The aminopropanone (6 grams) and ethylamine (10 ml.) were heated 40hours at 100 in a closed steel vessel. The reaction mixture was cooled,transferred to a round bottom flask and the excess of ethylamine wasremoved under reduced pressure. The thick brown oilyN-ethyl-beta-butylimine-alpha, alpha-dimethyl-pchlorophenethylamine wasanalyzed by infrared spectroscopy. A strong imine absorption occurred at6.05 microns and a small carbonyl absorption appeared at 5.95 microns.The crude imine was dissolved in ethanol ml.) and saturated withhydrogen sulfide with stirring. The light yellow dimercapto compound wasprecipitated, filtered, and slurried in ethanol ml.). The productdimercapto compound was separated again, and dried in vacuo at roomtemperature. The yield of dimercapto compound was 5.1 grams (70 percent)calculated on the aminopropanone), melting point 143-l45, decomposition.

Analysis: Calculated for C H NC1S C, 52.24; H, 6.58; N, 5.08; S, 23.25.Found: C, 52.98; H, 6.79; N, 4.83; S, 22.39.

All attempts to crystallize this compound were unsuccessful. Thecompound is insoluble at room temperature in common solvents, such asacetonitrile, ethanol, methanol, chloroform and benzene. Solution of thecompound by heating in the presence of these solvents results in theliberation of hydrogen sulfide, indicating the formation of thetrithiolane. The compound is slightly soluble in dimethylsulfoxide anddimethylformamide at room temperature but evolution of hydrogen sulfideagain occurs, indicating that the formation of the trithiolane occurs inthe solution process. An analytical sample was prepared by multiplewashing with cold ethanol.

The antimalarial compounds of the present invention have been shown tobe effective in the treatment of malaria-infected (interperitonealinjection of Plasmod in bergei) mice. The mice employed were inbred[CR/Ha Swiss mice and the antimalarial compounds were injectedsubcutaneously in solution or suspension in sterile sesame oil, peanutoil, or other pharmaceutically acceptable oil. The effectiveness of theantimalarial compounds is measured by the increase in life of the micerelative to untreated controls.

The results for three dimercapto compounds are shown in Tables I, 11 and111. The results show that the life span of the malaria-infected mice issignificantly prolonged and that, at certain dose levels, the mice areconsidered to be cured of malaria. It is significant that no toxicdeaths are reported even at the highest dosages, i.e., 640 milligramsper kilogram of body weight. The results for two trithiolanes arereported in Tables 1(a) and 11(a). While these compounds are lesseffective than the dimercapto compounds, the survival time of themalaria-infected mice is prolonged significantly; in one case (Example2), one or more of the mice survived 14 or more days, indicatingeffective activity of the compound as indicated by the conventionaldesignation of Active.

TABLE 1 Alpha, alpha-dimethyl-beta, beta-d1mercapto-N-butylphenethylamine (Example 1) No. 01 6 Dose Dally mortality 1 2 3 4 5 testsAnimal N 0. Sex days Rx Route (mg/kg.) (day/No.) Cures MSTI MS'IC T-C'Iox MSTX Result 1.. Mice 5 F 3 SC 40 06/02 07/03 00 6.6 6.2 .4 00 001.. do 5 F 3 SC 06/02 07/02 08/01 00 6.8 6.2 .6 00 00 1 d0 5 F 3 SC 64013/01 14/01 17/01 02 .0 6.2 00 00 Alive after 1 do 5 F 3 SC 640 13/0114/01 17/01 y g/0125411 00 17.6 0.2 11.4 00 00 Active.

No. of 6 Dose Daily mortality 1. 2 3 4 5 tests Animal N0. Sex days RxRoute (mg./kg.) (day/No.) Cures MST'I MSTC T-C 'Iox MS'IX Result 5 F as6 "16o (Te/651F702 to 6.4 0.0 .2" e F 3 SC 320 06/02 07/03 00 6. 6 6.6.0 00. 00 5 F 3 SC 640 12/01 13/01 14/01 02 .0 6.6 00 00 Alive alter 114 days. 1. Mean survival time treated mice (days). 2. Mean survivaltime control mice (days). 3. Change in survival time (days). 4. Toxicdeaths. 5. Mean survival time toxicity. 1 Number M 46 94 e e l we? 7 341 31591. .1

TABLE 1(a)2,5-diphenyl-2,5-bis-2-N-butylamlno-isopropyl-1,3,4-trlthluleno(Example 1) 6 days Dose Dail 1 2 3 4 5 Animal No. Sex Rx Route (mg./kg.)mortality (clay/No.3 Cures MSTT MS'IO '1-() Tax MSTX 5 M 3 SC 40 06/0207/02 08/01 00 6.8 6.1 0. 7 00 00 5 M 3 SC 160 07 03 08/02 00 7.4 6. 11.3 00 00 5 M 3 SC 640 08/01 09/02 10/02 00 0.2 6.1 3.1 00 00 5 M 3 SC06/04 07/01 00 6. 2 6. 1 0. 1 00 00 5 M 3 SC 06/03 07/02 00 6. 4 6. 10.3 00 00 5 M 3 SC 06/03 07/02 00 6. 4 6. 1 0. 3 00 00 5 M 3 SC 06/0107/03 03/01 00 7.0 6. 1 0.9 00 00 5 M 3 SC 320 06/01 07/02 08/01 09/0100 7.4 6.1 1.3 00 00 5 M 3 SC 640 09/03 10/02 00 9. 4 6. 1 3.3 00 00'E?lE9 1??!1915... u WWW 7 TABLE II Alpha, elpha-dimethyl-beta,bete-dimercapto-N-butyl-4-chlorophenethylemine (Example 2) N o. 6 DoseDaily mortality 1 3 4 5 tests Animal N0. Sex days Rx Route (mg./kg.)(day/No.) Cures MSTT MSTC T-C Tox MSTX Result M 3 SC 10 06/03 07/02 006.4 6. 2 0. 2 00 00 M 3 SC 20 06/03 07/02 00 6. 4 6. 2 0. 2 00 00 M 3 SC40 06/03 07/01 08/01 00 6. 6 6. 2 0.4 00 00 M 3 SC 80 06/03 07/01 08/0100 6.6 6.2 0.4 00 00 M 3 SC 09/01 11/02 13/02 00 11.4 6.2 5.2 00 00 M 3SC 320 11/02 12/01 13/01 14/01 00 12.2 6.2 6.0 00 00 M 3 SC 640 14/0117/02 19/01 01 16.8 6. 2 10.6 00 00 Cure. M 3 SC 2. 06/04 07/01 00 6. 26. 2 0. 0 00 00 5 M 3 SC 6.00 06/04 07/01 00 6.2 6. 2 0.0 00 00 m eem;$9 M1 A W M m w.

TABLE 11(3)2,5-di-4-chlor0pheny1-2,5-bis-2-N-butyleminoisopr0pyl-l,3,4-trlth1o1ene(Example 2) 6 Dose Dally mortality 2 3 4 5 No. of tests Animal No. Sexdays Rx Route (mg/kg.) (day/No.) Cures MST'I MSTO T-C Tox MSTX Result 5'M 3 SC 40 06/03 07/02 00 6. 4 6. 1 .3 00 00 5 M 3 SC 160 08/01 09/0110/01 00 10.0 6.1 3.9 00 00 11/01 1 /01 5 M 3 SC 640 10/01 13/01 14/0300 13.0 6.1 6.9 00 00 Active. 5 F 3 SC 20 06/03 07/02 00 6. 4 6. 1 3 6000 5 F 3 SC 40 06/02 07/03 00 6. 6 6. 1 6 00 00 5 F 3 SC 80 06/02 07/0300 6. 6 6. 1 5 00 00 5 F 3 SC 160 06/01 07/8} 00 9.0 6.1 2.9 00 00 11 5F 3 SC 320 12/02 13/02 14/01 00 12.8 6. 1 6.7 00 00 Active. 5 F 3 SC 64012/02 13/01 14/01 00 13.2 6. 1 7.1 00 00 D0.

See Notes 1 to 6, Table I.

TABLE III Alpha, alpha-dimethyl-bete,betel-(iimereepto-N-ethyl-4-chlorophenethylemine (E xemple 3) 0. of 6days D se Daily mortality ets Animal No. Sex Rx Route (mg/12g.)(day/No.) Cures IMSTT 2 MSTC 3 T-C 4 Tox 5MSTX Result 5 F 3 SC 40 08/0110/02 12/02 00 10.4 6.2 4.2 00 00 5 F 3 SC 160 12/02 13/01 14/02 00 13.06.2 6.8 00 00 Active. 5 F 3 SC 640 27/01 29/01 30/01 02 28.7 6.2 22.5 0000 Cum. 5 F 3 SC 20 06/03 08/01 10/01 00 7.2 6.2 1.0 00 00 5 F 3 SC 4010/01 11/01 12/02 13/01 00 11.6 6.2 5.4 00 00 5 F 3 SC 80 1 01 13 0214/62 00 13. 2 6.2 7.0 00 00 Active. 5 F 3 SC 160 13/02 14/01 15/0118/01 00 14.6 6.2 8.4 00 00 D0. 5 F 3 SC 320 16/01 18/01 20/01 22/01 0119.0 6.2 12.8 00 00 Cure. 5 F 3 SC 640 29/0132/01 03 30.5 6.2 24.3 00 00D0.

TABLE IV alpha, alpha-Dimethyl-beta,beta-dimercapto-N-butylphenethylamine EXAMPLE I P. cynomolgi l. 100mg/kg (oral) daily for 7 days 2 cured out of 2 animals 2. 3 l .6 mg/kg(oral) daily for 7 days 2 cured out of 2 animals 3. l0.6 mg/kg (oral)daily for 7 days no effect P. knowlesi l. 100 mg/kg (oral) daily for 7days 1 suppression out of 2 animals alpha, alpha-Dimethyl-beta,beta-dimercapto-N-butyl- (p-chlorophenyl)-ethylamine EXAMPLE II P.cynomolgi l. 100 mg/kg (oral) daily for 7 days,

2 cured out of 2 animals 2. 31.6 mg/kg (oral) daily for 7 days I cured,l marked suppression 3 l mg/kg (oral) daily for 7 days no effect P.knowlesi l. 100 mg/kg (oral) daily for 7 days 2 suppression of of 2animals 2. 3L6 mg/kg (oral) daily for 7 days I suppression out of 2animals P. knowlesi, a simian malarial parasite has recently been foundas the infecting agent in a human patient. (Resident Physician Vol. 14,No. 11 November 1968). Since considerable numbers of simians used aslaboratory animals are infected with malaria] parasites, the compoundsof the present invention provide a means for their treatment and theprevention of the infection of humans by female anopheline mosquitoesfrom the simians.

The foregoing description is only illustrative of the present inventionand it is intended that this invention be limited only by thehereinafter appended claims.

We claim:

1. The compound of the formula:

wherein R is phenyl and phenyl substituted with a halogen and wherein Ris lower alkyl.

2. The compound of claim 1 wherein R is 4- chlorophenyl.

3. The compound of claim 1 wherein R is 4- chlorophenyl and R is ethyl.

4. The compound of claim 1 wherein R is 4- chlorophenyl and R isn-butyl.

5. The compound of claim 1 wherein R is phenyl and R is n-butyl.

2. The compound of claim 1 wherein R is 4-chlorophenyl.
 3. The compoundof claim 1 wherein R is 4-chlorophenyl and R1 is ethyl.
 4. The compoundof claim 1 wherein R is 4-chlorophenyl and R1 is n-butyl.
 5. Thecompound of claim 1 wherein R is phenyl and R1 is n-butyl.